The present invention relates to salts of pioglitazone including water-soluble salts of pioglitazone, pharmaceutical compositions comprising these salts, and processes of using these salts.
Pioglitazone, chemically 5-[[4-[2-(5-ethyl-2-pyridinyl)-ethoxy]phenyl]methyl]-2,4-thiazolidinedione, of the formula (1):
is an antidiabetic agent. Pharmaceutical compositions comprising pioglitazone, as the hydrochloride salt, are marketed under the brand name ACTOS® (Takeda Chemical Ind.) for treatment of type II diabetes. Pioglitazone hydrochloride is generally considered to be an odorless white crystalline powder with a melting point of 193–194° C. It is known to be slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. However, pioglitazone hydrochloride dissolves well in N,N-dimethylformamide and dimethyl-sulfoxide.
EP 193256 and corresponding U.S. Pat. No. 4,687,777 disclose a class of thiazolidinedione derivatives and specifically disclose pioglitazone. These documents also disclose that the thiazolidinedione derivatives may be converted to a pharmacologically acceptable salt by using an acid or a base. The classes of acid salts include mineral salts (e.g., hydrochloride, hydrobromide, sulfate, etc.), organic acid salts (e.g., succinate, maleate, fumarate, malate, tartrate, etc.), and sulfonates (e.g., methanesulfonate, benzenesulfonate, toluenesulfonate, etc.). The base salts include alkali metal salts, e.g., sodium salt, potassium salt, and alkaline earth metal salts, e.g., calcium salt, etc. The examples in these documents include isolating pioglitazone as a base and as a sodium salt; see Examples 1(d) and 1(e), respectively, of U.S. Pat. No. 4,687,777.
Pioglitazone hydrochloride exhibits properties that make it suitable for many pharmaceutical purposes. It is an easily handled crystalline material, stable at room temperature and under moisture. However, it is extremely insoluble in water and is not suitable for making aqueous pharmaceutical solutions.
It would be desirable to have a water-soluble salt of pioglitazone for manufacturing and/or formulation purposes. For example, such a salt could be useful in making liquid pharmaceutical dosage forms, for instance oral solutions or injectable formulations.